One of the main obstacles inhibiting HIV eradication is a population of latently infected T cells. Although small, the latent population is extremely stable and resistant to current antiretroviral therapies. Upon withdrawal of antiretroviral therapy, HIV derived from the latent reservoir is able to rekindle infection and renew progression to acquired immunodeficiency syndrome (AIDS). Consequently, viral eradication will be dependent on therapeutic strategies to specifically target and clear the latent reservoir. However in order to develop these approaches, a greater understanding of factors that control viral latency is needed. Efforts in this regard have been hampered by the lack of a suitable in vitro primary T cell model of latency. The studies proposed herein will utilize a new in vitro model to characterize multiple aspects of HIV latency including defining viral and host factors that influence viral latency, and to identify agents that may prove useful in an "activation/elimination" strategy to purge latent reservoirs. To accomplish these goals, we propose the following Specific Aims: 1. To further characterize, optimize and adapt a primary cell in vitro model for HIV latency to study activation and elimination of latent virus;2. To develop a high-throughput screening method to identify additional agents that activate or inhibit activation of latently infected primary cells;3. To determine the role of viral accessory proteins in activation or formation of latent virus;4. Determine the role T regulatory cells play in viral latency. These studies will define host and viral factors influencing the latent T cell reservoir, and develop strategies to eliminate this reservoir.